Compared to men, women are at an increased risk of smoking-related morbidity and mortality. Sex hormones have been implicated in both the animal and clinical literature as having an effect on addictive behaviors. In clinical literature on tobacco use, our work along with others has demonstrated that the luteal phase (high progesterone) is associated with decreased smoking-related symtomatology and improved smoking cessation outcomes. These data suggest that progesterone (PRO) may enhance smoking cessation. Impulsivity is another factor that may impact smoking behavior as smokers are typically more impulsive than non-smokers. Further, among those who attempt to quit smoking, those who relapse have higher levels of impulsivity. Interestingly, clinical data indicates the association between impulsivity and smoking behavior may vary by sex. Further, data from the animal literature suggest that PRO may reduce impulsive behavior. Therefore, the objective of this project is to examine the interplay of PRO, impulsivity and sex differences in smoking cessation. Specifically, our primary aim is to investigate sex differences in the effect of exogenous PRO compared to placebo on impulsivity and smoking cessation. We will address this specific aim by conducting a double-blind randomized smoking cessation trial including female and male smokers randomized into one to either active or placebo PRO. The design (paralleling Project II) provides a unique opportunity to delineate sex differences and PRO effects in smoking cessation. If our hypotheses are confirmed, the results of this study could directiy advance the literature on the role of sex hormones in addictive behaviors. Further, this study has the potential to inform new and innovative smoking cessation intervention treatments via the delivery of exogenous hormones. RELEVANCE (See instructions): Despite much effort, there are not yet highly effective approved medications for the direct treatment of cocaine and nicotine dependence. This SCOR will carry out interdisciplinary and translational investigations to identify pharmacological interventions targeting behaviors impaired in nicotine and cocaine dependent subjects to enhance the effectiveness of existing behavioral treatments for addiction.